First-degree relatives of NIDDM patients have an ∼40% lifetime risk of developing diabetes, and insulin resistance is the best predictor. However, insulin resistance is altered by many other factors, including age, diet, exercise, and medications. To investigate the metabolic and endocrine alterations associated with insulin resistance when all the above confounding factors are excluded, we examined the first phase of insulin secretion and insulin sensitivity in 49 white normoglycemic (4.99 ± 0.51 vs. 4.95 ± 0.41 mmol/l) nonexercising lean (BMI, 24 ± 3 vs. 23 ± 2 kg/m²; 105 ± 3 vs. 104 ± 3% of ideal body weight) offspring of NIDDM patients. These subjects were compared with 29 matched healthy control subjects by means of an intravenous glucose bolus (0.3 g/kg body wt), immediately followed by a euglycemic-hyperinsulinemic (∼420 μmol/l) clamp, along with lipid and amino acid profiles. The offspring showed fasting hyperinsulinemia (40.6 ± 15.8 vs. 30.9 ± 13.6 μmol/l; P = 0.005) and higher free fatty acid (FFA) levels (582 ± 189 vs. 470 ± 140 μmol/l; P = 0.007), whereas triglycerides, total cholesterol, and HDL and LDL cholesterol levels were comparable with those of control subjects. Alanine (320 ± 70 vs. 361 ± 73 μmol/l; P = 0.017), serine (P = 0.05), and glutamine and glycine (P = 0.02) were lower in the offspring than in the control subjects, whereas branched-chain amino acids (343 ± 54 vs. 357 ± 54 μmol/l; P = 0.28) were not different. Insulin sensitivity was lower (4.86 ± 1.65 vs. 6.17 ± 1.56 mg · kg⁻¹ · min⁻¹; P = 0.001), and an inverse correlation with fasting FFAs in the offspring (adjusted R² = 0.21, P = 0.0005), but not in control subjects (adjusted R² = 0.03, P = 0.368), was found. Because insulin sensitivity in the offspring appeared to be a mixture of three distributions, they were subdivided into three subgroups: very low, low, and normal insulin sensitivity (20, 47, and 33%, respectively). The same alterations in amino acid and FFA metabolism were observed in the very low and low subgroups but not in the normal subgroup. The first phase of insulin secretion appeared to compensate significantly for insulin resistance in the low subgroup versus the normal subgroup and controls, but was inappropriately low in the subgroup with very low insulin sensitivity considering its degree of insulin resistance. In conclusion, lean insulin-resistant offspring of NIDDM parents showed 1) trimodal distribution of insulin sensitivity, 2) high fasting plasma FFA concentrations, 3) an inverse correlation between insulin sensitivity and FFA concentration, 4) low plasma gluconeogenic amino acid concentrations, and 5) defective insulin secretion when related to insulin sensitivity in the subgroup of very resistant offspring. These results suggest that, in this white population, insulin sensitivity may be determined by a single major gene and that alterations in FFA metabolism may play a role in the pathogenesis of NIDDM.